title: 22,23-Epoxy-2-aza-2,3-dihydrosqualene derivatives: potent new inhibitors of squalene 2,3-oxide-lanosterol cyclase.
abstract: Two new azasqualenoid derivatives, bearing a 22,23 epoxidic function, were synthesized, to obtain more efficient, competitive inhibitors of the enzyme squalene 2,3-oxide-lanosterol cyclase (EC 5.4.99.7). The activities of 22,23-epoxy-2-aza-2,3-dihydrosqualene 4 and of its N-oxide derivative 5 were studied using rat and pig liver microsomal preparations and compared with a pig liver partially purified squalene 2,3-oxide-lanosterol cyclase. The activities of compounds 4 and 5 were compared in the different enzymatic preparations with the activities of 2-aza-2,3-dihydrosqualene 2 and of 2-aza-2,3-dihydrosqualene N-oxide 3 previously studied only with rat liver microsomes. Using a solubilized, partially purified squalene 2,3-oxide cyclase, all the compounds exhibited a non-competitive type of inhibition. As the previously suggested mechanism of inhibition does not account for this kinetic behaviour, a new hypothesis is suggested.
authors.affiliation: Istituto di Chimica Farmaceutica Applicata, Università di Torino, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Viola
authors.forename: M
authors.initials: M
authors.lastname: Ceruti
authors.forename: G
authors.initials: G
authors.lastname: Balliano
authors.forename: O
authors.initials: O
authors.lastname: Caputo
authors.forename: L
authors.initials: L
authors.lastname: Cattel
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D013185:Squalene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013552:Swine
chemical_list: D004852:Epoxy Compounds; C067257:22,23-epoxy-2-aza-2,3-dihydrosqualene; C067258:22,23-epoxy-2-aza-2,3-dihydrosqualene N-oxide; D013185:Squalene; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase